Variants in theGH-IGFaxis confer susceptibilityto lung cancer

Abstract

We conducted a large-scale genome-wide association study in UK Caucasians to identify susceptibility alleles for lung cancer, analyzing 1529 cases and 2707 controls. To increase the likelihood of identifying disease-causing alleles, we genotyped 1476 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 871 candidate cancer genes, biasing SNP selection toward those predicted to be deleterious. Statistically significant associations were identified for 64 nsSNPs, generating a genome-wide significance level of P = 0.002. Eleven of the 64 SNPs mapped to genes encoding pivotal components of the growth hormone/insulin-like growth factor (GH-IGF) pathway, including CAMKK1 E375G (OR = 1.37, P = 5.4 × 10 ) and GHR P495T (OR = 12.98, P = 0.0019). Significant associations were also detected for SNPs within genes in the DNA damage-response pathway, including BRCA2 K3326X (OR = 1.72, P = 0.0075) and XRCC4 I137T (OR = 1.31, P = 0.0205). Our study provides evidence that inherited predisposition to lung cancer is in part mediated through low-penetrance alleles and specifically identifies variants in GH-IGF and DNA damage-response pathways with risk of lung cancer.[Supplemental material is available online at www.genome.org.]Lung cancer is the most common cancer in the world and represents a major public health problem, accounting for ∼1.2 million cancer-related deaths worldwide each year (Parkin et al. 2005). Tobacco smoking is acknowledged to be the major risk factor for lung cancer, contributing to a 10-fold increase in risk in long-term smokers compared with nonsmokers (Doll and Peto 1981). Other environmental risk factors include exposure to radiation, asbestos, heavy metals, polycyclic aromatic hydrocarbons, and chloromethyl ethers (IARC 1986).Lung cancer is frequently cited as a malignancy solely attributable to environmental exposure. However, it has long been postulated that individuals may differ in their susceptibility and there is increasing evidence from epidemiological studies for a familial risk (Matakidou et al. 2005). Direct evidence for a genetic predisposition is provided by the increased risk of lung cancer associated with a number of rare Mendelian cancer syndromes, such as carriers of constitutional tumor protein p53 (TP53) (Hwang et al. 2003) and retinoblastoma (Sanders et al. 1989) gene mutations, as well as in patients with Bloom's (Takemiya et al. 1987) and Werner's syndromes (Yamanaka et al. 1997).The genetic basis of inherited susceptibility to lung cancer outside the context of the rare Mendelian cancer predisposition syndromes is at present undefined, but a model in which dominantly acting, high-risk alleles account for all of the excess familial risk seems unlikely. An alternative hypothesis about the allelic architecture of lung cancer susceptibility proposes that most of the genetic risk is caused by low-penetrance alleles. This hypothesis implies that testing for allelic association should be a powerful strategy for identifying lung cancer predisposition alleles.We sought to identify novel ...

Inherited Predisposition of Lung Cancer: A Hierarchical Modeling Approach to DNA Repair and Cell Cycle Control Pathways

“…The common polymorphism R188H was also shown to have a small effect on XRCC2 function and cell survival after DNA damage (31). Only limited studies have been conducted to assess the association between XRCC2 R188H and lung cancer risk and the results have been inconsistent (26,32,33). Our observations of XRCC2 188H allele among current smokers and small-cell carcinoma are compatible to the previous experimental evidence.…”

Mutations in Fanconi anemia genes and the risk of esophageal cancer

“…Although the BRCA2 p. Lys3326X mutation does not appear to predispose to breast cancer (Mazoyer et al 1996), individuals with this specific truncating mutation have been reported to be at increased risk for familial pancreatic cancer (OR = 4.8, 95% CI = 1.3-19, P \ 0.01) (Martin et al 2005) and for lung cancer (OR = 1.72, 95% CI = 1.15-2.57, P = 0.007) (Rudd et al 2006). To our knowledge, the variant has not been seen elsewhere in esophageal cancer patients.…”

Association between the TP53BP1 rs2602141 A/C Polymorphism and Cancer Risk: A Systematic Review and Meta-Analysis

“…As the reason for few studies were performed and there were many meta-analysis related on TP53 gene polymorphism and cancer risk (Weng et al, 2012;Zhao et al, 2013), we could not use meta-analysis to analyze the relationship between TP53BP1 rs2602141 A/C polymorphism combined with TP53 gene polymorphism and cancer. In addition, Rudd et al (Rudd et al, 2006) and Truong et al (Truong et al, 2010) found that rs2602141 polymorphism was associated with lung cancer risk. However, because lack of sufficient data from these two studies, we could not include these studies in this metaanalysis.…”